Addicted from the first cigarette

New findings show that cigarette addiction can develop incredibly quickly. But the research could also lead to new ways of treatment that will make withdrawal easier

By Joseph R. DeFerranza

When I trained in family medicine, I was taught the popular belief about nicotine addiction. Doctors have long believed that people smoke mainly because they enjoy smoking and that they develop a psychological dependence on this pleasure. And because you get used to the effects of nicotine, the frequency of smoking increases. When the frequency of the habit reaches the threshold of about five cigarettes per day, nicotine is in the blood all the time, and only then can the physical addiction begin, usually after smoking thousands of cigarettes for years. Within a few hours of the last cigarette, the addicted smoker experiences the symptoms of nicotine withdrawal: restlessness, irritability, difficulty concentrating, etc. According to this view, those who smoke less than five cigarettes a day are not addicts.

Armed with this knowledge, I met with that well-known patient who had not read the book. During a routine check-up, one teenage girl told me that she could not stop smoking even though she had only started two months earlier. I thought that this patient was nothing but the exception that proves the rule that it takes years to develop an addiction. But my curiosity was piqued and I went to the local high school to find out about the smoking habits of the students. There, a 14-year-old girl told me that she made two serious attempts to quit smoking, and failed both times. This was a novelty, as the girl had started smoking only two months before and smoked only a few cigarettes a week. When she described her withdrawal symptoms, the story sounded like the complaints of a person who smokes two packs of cigarettes a day. The rapid development of these symptoms, without smoking every day, contradicted most of what I thought I knew about nicotine addiction in those days. And when I traced the source of the conventional wisdom mentioned here, I found that everything I learned was nothing but an unsuccessful educated guess.

Thanks to funding I received from the American Cancer Institute and the American Institute on Drug Abuse (NIDA), I have been able to research over the past ten years how nicotine addiction develops in novice smokers. Today I know that the addiction model described in the first paragraph is completely false. My research establishes a new hypothesis: little exposure to nicotine, even smoking one cigarette, is able to change the structure of the brain and its nerve cells so that a craving for smoking is created. This understanding, if proven to be correct, may open up for the researchers, when the day comes, good ways to develop new drugs and other treatments that will help people get rid of this habit.

The loss of free will

When I began this research in 1997 with my colleagues at the University of Massachusetts Medical School at Worcester, the first challenge we faced was developing a reliable tool to diagnose the first symptoms of addiction as they develop. In my opinion, the distinguishing characteristic between an addict and a non-addict is the loss of free will, or autonomy, that is, the smoker must make an effort to stop smoking or the break is unpleasant. To find out if such a loss does occur, I compiled a list of questions to examine the signs of nicotine addiction. A positive answer to one of the questions on the list shows that the addiction has already begun. The list, which has been translated into 13 different languages ​​to date, is the most carefully validated estimate of nicotine addiction. (And it can easily be converted to test addiction to other drugs.)

We distributed the questionnaire to hundreds of teenagers, several times over three years. It turned out that the rapid development of addiction is quite common. It was found that the highest probability of the beginning of addiction is in the first month after the first cigarette. Any of the signs on the list, including a craving for cigarettes and failed attempts to quit, can appear already in the first weeks of smoking. The first signs of addiction began when teenagers smoked an average of only two cigarettes a week. These findings shattered conventional wisdom and provided a wealth of insight into how addiction begins. But when I presented the findings in February 2000 and claimed that some teenagers were suffering from addiction symptoms after smoking just one or two cigarettes, most of my colleagues looked at me like a professor who didn't understand the book he was reading.

Many ordinary people have told me that based on their experience they know I am on the right track. But even if there were scientists who believed me, they were not willing to risk their good name and admit it publicly. Skepticism celebrated. How could an addiction start so quickly? How is it possible that withdrawal symptoms are observed in smokers whose nicotine level in their blood is not constant?

Later my position was proven, when teams of researchers led by Jennifer Olflin from McGill University, Dennis Kendall from Columbia University, and Robert Scragg from the University of Auckland in New Zealand, received in a study they conducted the same results that I received in my research. A dozen studies have established and established that nicotine withdrawal symptoms are common in new smokers. 10% of those who experience addiction symptoms feel them within two days of the first cigarette they smoked, and 35%-25% feel them after a month or less. In a very comprehensive study done on young people in New Zealand, it was found that in 25% of them the symptoms appeared after smoking one to four cigarettes. And if symptoms described in the questionnaire appear in a teenager, the chance increases almost 200 times that he will increase the frequency and start smoking every day.

These results raise the question of how nicotine from a single cigarette changes the brain enough to cause the onset of addiction. Studies done in laboratory animals have revealed that chronic exposure to nicotine in high doses, doses equivalent to smoking a pack of up to three packs of cigarettes a day, results in an increase in the number of nerve receptors that have a strong affinity for nicotine. In post-mortem examinations of smokers, such an increase is seen, at a rate of 50% to 100%, in the frontal lobe, hippocampus and cerebellum.

I convinced Theodore Slotkin of Duke University to find out what the minimum level of nicotine exposure is needed to trigger the increase in receptor levels. His team of experimenters gave rats small doses of nicotine (in amounts equivalent to one to two cigarettes) for several consecutive days, and on the second day they already discovered an increase in the amount of receptors in the hippocampus, which is an area of ​​the brain involved in long-term memory. Then, Arthur Brody and his colleagues from the University of California in Los Angeles discovered that one cigarette has an amount of nicotine capable of binding to 88% of the nicotine receptors in the brain. Although it is not known what role the increase in the level of receptors plays in addictions, these studies show that withdrawal symptoms in adolescents are physiologically possible as early as two days after the first cigarette smoked.

Addiction researchers believe that withdrawal symptoms arise from the body's attempts to maintain a state of balance (homeostasis) of substances and functions after drug use. For example, there are addictive drugs that increase the production of neurotransmitters, chemicals that transmit signals from one nerve cell to another, and in response the body activates an adaptive mechanism that inhibits these chemicals. But when the addict stops using the drug, the delay becomes excessive and withdrawal symptoms appear. It is known that this adaptation, related to withdrawal symptoms, can develop quickly after the first cigarette, as other addictive drugs, such as morphine for example, cause such changes very quickly. But most long-time smokers know that they can only go without smoking for an hour or two before craving another cigarette, while novice smokers can go weeks without smoking. Amazingly, at the beginning of addiction, one cigarette is enough to suppress withdrawal symptoms for weeks, even when the nicotine has already been eliminated from the body after a day.

The explanation for this interesting fact is that the results of flooding the brain with nicotine leave their mark long after the flooding itself. Nicotine activates brain circuits that work through biochemical compounds such as acetylcholine, dopamine, GABA, glutamate, noradrenaline, opioid peptides and serotonin. In rats, one dose of nicotine is sufficient to increase noradrenaline synthesis in the hippocampus for at least a month, and the effect of nicotine on some neurological and cognitive functions also lasts for weeks. Although it is not known if any of these phenomena are related to withdrawal, they prove that the effect of nicotine continues long after it has been removed from the brain.

The symptom-free period between the last cigarette and the onset of withdrawal symptoms is called Latency to Withdrawal (LTW). In beginners smokers, the LTW is long, and one cigarette every few weeks is enough to overcome withdrawal symptoms. However, from smoking more and more, tolerance develops and the effect of each cigarette decreases, the LTW shortens, and the frequency of smoking necessary to prevent withdrawal symptoms increases. This shortening of the LTW is called dependence-related tolerance. Unlike the adaptation of the homeostatic mechanisms that can occur immediately, the tolerance that characterizes dependence usually develops very slowly. Sometimes years pass before the LTW shortens enough to force the smoker to five cigarettes a day. In fact, withdrawal symptoms are the cause of heavy smoking in the long term, and not the other way around as we have thought so far.

It's time for a new theory

I have always questioned the idea that smokers are actually addicted to the pleasure of smoking, because some of my most addicted patients hated the habit. If the accepted opinion is correct, shouldn't the most addicted of all also enjoy the most? Eric Molchan from NIDA showed that teenagers whose addiction got stronger and stronger actually reported a decreasing pleasure from smoking. A new theory was needed to explain these discoveries.

While trying to understand how nicotine addiction starts so quickly, I encountered a contradiction: the only action that nicotine does, at least to the innocent observer, is to calm the craving for more nicotine. However, only those who have already been exposed to nicotine crave it. How is it possible that the same drug both arouses the craving and satisfies it? I began by hypothesizing that the direct, immediate action of nicotine is to calm the craving, and that this action intensifies and becomes extreme because the additional doses of nicotine provoke a stronger reaction than the first dose. (This phenomenon, called excitement or sensitization, characterizes all addictive drugs.) As a result, the brain may quickly develop adaptive mechanisms to counteract the action of nicotine, thus restoring the state of balance. But when the nicotine wears off, these adaptations cause a craving for another cigarette.

According to this sensitization-homeostasis theory, nicotine is not addictive because of the pleasure it causes, but simply because it suppresses the craving. Since nicotine stimulates nerve cells, I described to me that it activates nerve cells in the system that suppresses craving in the brain. The activation of this supposed system will suppress the activity of a complementary system, the one that produces the longing. According to the theory, the natural role of the craving production system is to receive sensory input (such as sights or smells, for example), compare it with memories of rewarding objects (like food, for example), and produce a craving that drives appetitive behavior (eating, for example). The function of the craving suppression system is to declare satiety, so that the animal will stop the appetitive behavior at the appropriate time.

Since the body tries to maintain a balance between these two systems, the dampening that nicotine creates on the action of the craving system causes the development of adaptations that increase its action. During withdrawal, when the sedative effect of nicotine wears off, the craving production system remains in an excited state, which causes a strong desire to smoke another cigarette. These changes in brain activity occur because of a rapid change in the receptor configurations of nerve cells, which explains why adolescents crave cigarettes even if they have only smoked one cigarette in their lifetime.

The first confirmation of this model was provided by many studies that used magnetic resonance imaging (fMRI) of human brain function and showed that craving caused by an external signal such as nicotine, alcohol, cocaine, opiates or chocolate increases metabolic activity in the anterior cingulate ridge of the brain and elsewhere in the frontal lobe of the brain This finding shows that there is a system that produces longing. Also, researcher Hyun-Kook Lim and his colleagues from the Korea Medical College recently discovered evidence that nicotine suppresses the operation of this system. They showed that pre-administration of nicotine can block the pattern of activation of the brain regions that characterizes the craving evoked by an external signal in humans.

The sensitization-homeostasis model can also explain the tolerance that characterizes addiction. Repeated suppression of activity in the craving-producing system results in another homeostatic adaptation that induces craving by shortening the duration of nicotine's inhibitory effect. As mentioned, tolerance develops much more slowly than the adaptation that characterizes withdrawal, but once tolerance has developed, it takes root well. Although it usually takes two years or more before an adolescent begins to need five cigarettes a day, I have noticed that my patients, who stopped smoking and then started again, returned to smoking as frequently as before the cessation after only a few days, even after a long period of abstinence.

Robert Wellman of Fitchburg State College and I investigated this phenomenon in a study in which 2,000 smokers were asked how much they smoked before they quit, how long they had not smoked, and how much they smoked immediately when they started smoking again. Smokers who returned to smoking after three months of abstinence resumed the habit about 40% more often than before they quit, which means their LTW was prolonged. We believe that the craving-free period between cigarettes is longer because the adaptation that characterizes withdrawal disappears in the first weeks of abstinence. However, when you go back to smoking, this adaptation returns and develops quickly, and within a few weeks, those who go back to smoking find that they are once again smoking as often as they were used to before the break.

We also found, however, that abstinence for more than three months had almost no additional effect on LTW. Even after years of abstinence, those who return to smoking initially smoke about 40% of what they smoked before, usually six to seven cigarettes a day. This finding shows that the strength of endurance is constant: in a smoker who has stopped and returned, one cigarette will not satisfy the craving as it will in a beginner smoker. In other words, a smoker's mind never returns to its pre-smoking state.

But if addictive tolerance stimulates the craving system into action, and never fully wears off, why don't ex-smokers continue to crave a cigarette forever? The subjects in our studies could not say why, in the end, their craving for nicotine decreased, so I checked what the sensitization-homeostasis theory would predict in this regard. It makes sense, I told myself, that ex-smokers would develop adaptive mechanisms associated with abstinence and mimic the action of nicotine, that is, inhibit the craving production system and restore the state of balance. Quitting smoking will therefore not result in a simple return to normal brain function, but will result in the beginning of a dynamic period of neural plasticity, in which new adaptations will appear in the brain of the smoker who has quit. Because of these adaptations, the brain of an ex-smoker is not the same as the brain of a smoker, nor that of a non-smoker.

To put this prediction to the test, Slotkin and his colleagues examined the brains of rats before they were exposed to nicotine, during exposure to it, during withdrawal from it, and long after withdrawal. They discovered conclusive evidence of changes in the function of the neurons in the cerebral cortex that transmit signals through acetylcholine and serotonin. These changes happened only after an acute withdrawal period. As expected, the brains of the "ex-smoker" rats developed unique adaptations that "smoker" or "non-smoker" rats did not. At the Catholic University of Korea School of Medicine, Hye-jin Lim and colleagues tracked nerve growth factor and found evidence of brain remodeling in people who quit smoking. In the brains of smokers who stopped smoking for two months, the amount of this factor increased threefold.

If so, abstinence-related adaptation likely counteracts tolerance-related adaptation by suppressing the craving-producing system until it eventually stops prompting the ex-smoker to light up a cigarette. However, the stimulating signals for smoking provided by the environment may increase and stimulate the craving, and if the smoker who has been abstinent for a long time succumbs to the urge to smoke, even once, the nicotine will again cause a strong suppression of the craving production system. Then the adaptation associated with abstinence will deteriorate the situation from bad to bad. Since this adaptation mimics the action of nicotine, it must be canceled to restore the state of balance; When the effect of nicotine wears off, the adaptation that characterizes the development of tolerance will remain without any competing factor to prevent it from activating the craving production system. The repeat smoker will feel a strong craving and will need six to seven cigarettes to satisfy it.

New hope for smokers

This model for describing addiction does not reflect the popular opinion at all. In my view, addiction is a physiological accident. Since so many careers have been built on the assumption that the root of addiction is psychological rather than physiological, I did not expect that my ideas would be welcomed.

If the sensitization-homeostasis theory is true or not, it is clear that the nicotine of one cigarette is enough to cause a reshaping of the brain. Some would argue that it is better to use certain criteria for a proper diagnosis of addiction, but today there is no doubt that teenagers suffer from many addiction symptoms very shortly after smoking the first cigarette in their lives. This finding highlights the need to increase government funding for anti-smoking advertising campaigns, funding that has been cut recently in the US.

In order to conduct a thorough and complete examination of my theory, which I have explained here in simplicity, researchers need a reliable method for diagnosing sensitization in humans. I worked with Jean A. King and her colleagues at the Center for Comparative Brain Imaging, trying to show nicotine sensitization in rats using fMRI. In the images comparing the brain's response to the first dose of nicotine and its response to the fifth dose, you see a radical change in brain functions in several areas, including the anterior cingulate ridge and the hippocampus. We recently received funding from NIDA to use fMRI to visualize sensitization in smokers, with the intention of determining, in due course, which brain regions are involved in the craving suppression system and the craving production system.

Our long-term goal is to find a drug that can bring about changes in these systems and cure or treat addiction. Although nicotine replacement therapy may double the chance of continuing abstinence, the majority of attempts to quit smoking still fail. The sensitization-homeostasis theory shows the need for a treatment that will alleviate the craving without causing compensatory reactions that could worsen it, in the long run. A better understanding of the addiction process could help researchers develop new treatments that could safely free smokers from nicotine's deadly grip.

key concepts

A new study refutes the popular belief that cigarette addiction does not develop until years of smoking. Studies in adolescent smokers show that addiction symptoms, such as withdrawal difficulties, cravings for cigarettes and failed attempts to quit smoking, sometimes appear in the first weeks of smoking.

To explain these findings, scientists have devised a new theory that assumes that the brain is in a hurry to develop adaptive mechanisms that contradict the effects of nicotine. The adaptation causes the withdrawal symptoms when the effect of nicotine wears off.

The results emphasize how important it is to increase government funding for anti-smoking advertising campaigns, especially those aimed at youth.

A new hypothesis

Fast addiction

Researchers offer a new theory that explains how withdrawal symptoms develop so quickly in first-time smokers. Although this model is controversial, it may in the future help to better understand cigarette addiction.

A healthy balance

In people who do not smoke, there is a balance between the brain systems whose role is to arouse craving and quench it. The craving production system brings about appetitive behavior (such as eating), and the craving suppression system stops this behavior when the person is satisfied (when he has finished eating, for example).

The first cigarette

Nicotine stimulates the craving suppression system until its action increases and far exceeds that of the craving production system. The brain tries to restore the lost balance through the rapid development of adaptations that increase the activity of the craving production system. (These changes are called withdrawal-related adaptations.)

weaning

When the effect of nicotine wears off, the craving suppression system is no longer stimulated, and returns to a relatively low level of activity. But the craving production system, reinforced by withdrawal-related adaptations, throws the brain off balance again and causes a strong craving for the only thing that can satisfy the craving: another cigarette.

Nicotine withdrawal

A collection of symptoms including longing, restlessness, irritability, impatience, difficulty concentrating and sleep problems.

Weaning latency

The symptom-free period between the last cigarette the addict smoked and the onset of withdrawal symptoms. This time period, the LTW, can shorten from a few weeks to a few minutes after years of tobacco consumption.

Endurance characterized by dependence

The mechanism that causes LTW to slowly shorten over time.

Abstinence-related adaptations

A mechanism that mimics the action of nicotine by suppressing the craving. It develops in ex-smokers to counteract the lingering effects of addictive tolerance.

About the author

Joseph R. DiFranza is a family physician who works at the University of Massachusetts Medical School in Worcester. Defranza has been troubling the rest of the tobacco industry for 25 years and is among the advocates of taking steps to prevent tobacco manufacturers from selling their products to teenagers. The research he conducted and the complaint he filed with the "Federal Trade Commission" led to the downfall of the infamous advertisement for Camel cigarettes starring Joe Camel. DeFrenza received a grant from the pharmaceutical company Pfizer to find out if his theory on cigarette addiction explains the effectiveness of drugs that help quit smoking.

Questionnaire for smokers

Researchers use the questionnaire in front of you to find out if adolescent smokers are indeed addicted to cigarettes. A positive answer to any of the questions means that the addiction has already begun:

• Have you ever tried to quit smoking and failed?
• Today you smoke because it is very difficult to quit?
• Have you ever felt like you are addicted to tobacco?
• Do you sometimes have a strong craving to smoke?
• Have you ever felt like you really needed a cigarette?
• Do you find it difficult to avoid smoking in places where smoking is prohibited, such as a school for example?
• When you tried to quit smoking (or, after a while of not using tobacco):
• Did you have trouble concentrating because of quitting smoking?
• Did you feel more comfortable getting angry because of quitting smoking?
• Did you feel the need or a strong urge to smoke?
• Did you feel nervous, restless or restless because of quitting smoking?

A closer look - nicotine in the brain

Recent studies provide evidence for the belief that nicotine causes rapid changes in the physiology of the brain. Gene A. King, from the Center for Comparative Brain Imaging of the University of Massachusetts Medical School, measured with the help of functional magnetic resonance imaging (fMRI) the levels of metabolic activity in the brains of rats that were dosed with nicotine, day after day, for five days. . The response to the first dose was relatively small (the red areas in the cross-section on the left), but the brain activity was much more vigorous (yellow) and diffused after the fifth dose (in the cross-section on the right). These findings show that the brain becomes sensitive to nicotine, undergoes excitement, sensitization, very quickly, which allows addiction to appear after only a few doses.